1,2,4-oxadiazine-3,6-triones

ABSTRACT

NEW 1,2,4-OXADIAZINE-ONES, USEFUL AS ALGICIDES, BACTERRICIDES AND FUNGICIDES, ARE OBTAINED BY REACTING AN N-HYDROXY-UREA AND A DIHALOGENATED ORGANIC DERIVATIVE HAVING HALOGEN ATOMS ON TWO ADJACENT CARBON ATOMS.

United States Patent C) 3,743,641 1,2,4-XADIAZINE-3,6-TRIONES DanielMakula and Monique Druet, Lyon, and Beatrice Gonthier, Caluire, France,assignors to Progil, Paris, France No Drawing. Original application Apr.1, 1970, Ser. No. 24,859, now Patent No. 3,696,099. Divided and thisapplication May 5, 1972, Ser. No. 250,568- Claims priority,appliggaiggsgirance, Apr. 3, 1969,

Int. Cl. C07d 87/52 US. Cl. 260-244 R 4 Claims ABSTRACT OF THEDISCLOSURE New 1,2,4-oxadiazine-ones, useful as algicides, bactericidesand fungicides, are obtained by reacting an N-hydroxy-urea and adihalogenated organic derivative having halogen atoms on two adjacentcarbon atoms.

This is a divisional of application Ser. No. 24,859 filed Apr. 1, 1970,now US. Pat. 3,696,099.

The present invention relates to new heterocyclic compounds comprisingoxygen and nitrogen in their ring, as well as their manufacture andtheir applications. It relates more especially to new oxadiazine-ones.

In the literature, compounds of this type have already been describedbut most of them are 1,3,5-oxadiazineones. To applicants knowledge theonly 1,2,4-isomers known until now are those bearing ketone groupseither in the -position or in the 3 and S-positions.

New 1,2,4-oxadiazine-ones have now been provided which answer thegeneral formula:

in which X and Y, identical or diflz'erent, represent the 0 II C.

function or the group in which R is hydrogen or CH;,, with the exceptionof the compounds in which X is equal to o R -ll and Y to JJH R and R-identical or different, indicate a lower alkyl residue or a phenylradical having possibly one or several substituents chosen amonghalogens, and nitro, alkyl, alkoxy, trifluoromethyl groups.

Hence the compounds of Formula I may be perhydro- 1,2,4oxadiazine-3-ones; 3,6-diones and 3,5,6-triones. Under ambientconditions they are usually present in the form of white or slightlycolored crystalline solids, usually soluble in common solvents, althoughsome of them are oils.

The heterocycles of Formula I are produced, in a general way, byreacting, in the presence of a base, a conveniently substitutedN-hydroxy-urea with a dihalogenated organic derivative having thehalogen atoms on two adjacent carbons. It is possible to indicate,without limiting the invention field by theoretical explanations aboutreaction mechanism, that there occurs first a condensation of thedihalogenated derivative and hydroxyurea, giving an O-substituted urea;then a cyclisation of 3,743,641 Patented July 3, 1973 this intermediaryproduct, which leads to the heterocycle. Each of these reactions occurwith the removal of a halogen atom. The total reaction may beschematized as follows:

ii 11'"; o O 1 ill N-Ri YG 2N-R1 x 0 its 3330 \4/ r""""1 N Hal H i N IR:

The N-hydroxy-ureas (b) used as raw materials are known type products,which may be obtained according to the usual techniques, for example byreaction of an N-substituted hydroxyl-amine with the convenientisocyanate. It is easily understood, with regard to Formula 1hereinabove, that the dihalogenated derivatives (a) used in the processaccording to the invention may be, respectively, according to thedesired final product, a 1,2-d1'halogenoethane; 1,2-dihalogeno-propane;2,3-dihalogeno-butane; halogeno-acetyl halide; a-halogeno-propionylhalide; oxalyl halide.

There are used quantities of reagents corresponding at least tostoichiometry. But, in order to obtain a more complete reaction and toavoid the formation of byproducts such as diureas, it is better tooperate with an excess of dihalogenated derivative, with regard toN-hydroxy-urea quantity, the same as possibly with a base excess.Reaction is advantageously achieved in the presence of an organicsolvent inert the operative conditions.

The general process according to the invention has variants, accordingto the nature of the used dihalogenated reagent. When this reagent is ahydrocarbon derivative, which leads to the obtaining of a monoketonicheterocycle, there is generally used as a base, an alkali metalhydroxide, which is advantageously introduced into the reaction mixtureas an aqueous solution. When using an acyl halide as a dihalogenatedreagent, to obtain dior triketonic heterocycles, use of an alkalinesolution must be avoided as it would give rise to hydrolysis of the acylhalide. So, it is convenient, in this latter case, to substitute foralkaline hydroxides, a tertiary organic base, for fixing hydrogenhalides, as for example triethyl-amine or pyridine. If acyl halide hasonly a radical Hal CO-, the reaction may be achieved in 2 stages: in thefirst stage, during which acyl halide is present in free state, thereaction is operated in the presence of a tertiary organic base; in thesecond stage, that is when the CO group of said acyl halide is linked tothe initial urea, it is possible to use again an alkaline solution inorder to achieve cyclisation.

In the same way, the organic solvent which may be used in the processvaries with regard to the peculiar dihalogenated derivative. If it is ahydrocarbon derivative it is possible to choose the solvent from amongaliphatic alcohols such as methanol or ethanol, aromatic hydrocarbonssuch as benzene, toluene, xylene, etc. If it is an acyl halide, the useof alcohols which would not be inert in operative conditions must beavoided and aromatic hydrocarbons are used or ketones, such as acetone,etc. Once the reaction has ended, the reaction mixture is first filteredif it has been carried out in the presence of organic base, in order toseparate the hydro-halogenide formed during the reaction. If the processhas been achieved in the presence of alkali metal hydroxide, filtrationis not obligatory. However it may be useful, as it permits removal, incase of need, of the diurea which could have been formed as a secondaryproduct. Then it is possible to wash the filtrate with an alkalinesolution in order to remove from it any trace of non-transformed initialN- hydroxy-urea. Then the desired heterocycle is isolated by methods ofknown type, as for example by precipitation with water of oxadiazine-oneor solvent evaporation. In this last case, the operation is followedwith a waterwashing, when reaction has been achieved in the presence ofan alkaline hydroxide in order to remove the alkali metal halide formedduring reaction. The final product may at last be recrystallized out ofa convenient solvent such as an alcohol, as methanol or ethanol, achlorinated aliphatic hydrocarbon such as chloroform, an aromatichydro-carbon such as benzene or a mixture of alcohol and water, or ofketone and water.

Formula I compounds according to the invention possess interestingbiocidal properties. Taken individually, they have been shown to beeflicient, either separately, or the most generally, simultaneously, forcombatting bacterian and fungic degradations the same as for destroyingor inhibiting algae growth. Moreover some of those bodies arenematocides. Besides, their pesticidal interest is increased by the factthat they are little toxic with regard to fishes and mammals. So, forexample, ichthyotoxicity, studied on trouts, of 2 methyl4-(3,4-dichlorophenyl) perhydro-1,2,4-oxadiazine-3,6-dione isnon-existent at the amount of p.p.m. (parts per million) in water, in a3 hour test. The LD of this heterocycle (lethal amount corresponding toa 50% death-rate of the animals submitted to the test), studied on mice,is about 650 mg./kg. LD of 4-methyl-2 phenylperhydro-1,2,4-0xadiazine-3- one is greater than 1000 mg./kg.

The polyvalent activity of several of those compounds makes those onesquite useful for some applications, for example, for water treatment,and especially of industrial water circuits, (simultaneous fight againstalgae, bacteria, fungi) or for the protection of materials such as forexample, glues (simultaneous fight against bacteria, fungi). Asfungicides they are especially interesting for the protection ofcellulosic materials such as wood, or textile fabrics and fibers, resinsand elastomers, paints, varnishes, etc.

The compounds according to the invention are usable, as biocidal agents,as such or according to the usual formulations, with regard tocontemplated uses. For example, they may be incorporated such as theyare in the material to be treated, the solid products being previouslyonly ground. They may also be applied by spraying or aspersion, in theform of liquid compositions, such as in aqueous suspensions ofemulsions, organic or hydro-organic solutions. In those last cases, itis possible to use as solvents, classical products such as hydrocarbons,for example toluene, xylene, petroleum cuts, alcohols, ketones forexample acetone, methylisobutylketone, etc.

Moreover the compositions based on those active materials may containvarious adjuvants such as solubilizing, dispersing, wetting, fixing,stabilizing agents, for example alkali pyrophosphates, soya lecithin,alkali metal lignosulfonates, carboxymethylcellulose, polyvinylicalcohol etc. Besides they may contain other biocides of known type.

The examples hereinafter illustrate the object of the invention.Examples 1 to 3 relate to the manufacture of heterocycles according tothe invention. The following examples emphasize their biocidal activity.

EXAMPLE I In a flask provided with a central stirring and an ascendingcooler, 140 gm. (0.75 mole) or 1,2-dibromo ethane and 500 ml. of ethanolwere boiled under reflux; then in about 1% h. there was added a solutionof 40 gm. of sodium hydroxide (1 mole) in 250 ml. of water, containing118 gm. (0.5 mole) of N-3,4-dichloro-pheny1N'- methyl N'-hydroxy-urea.Reflux was maintained during 2 hours after addition ended. Then theslightly cloudy solution was hot-filtered. After cooling, 1 litre ofice-water was added to the filtrate. The formed precipitate wasseparated by filtration and recrystallized out of chloroform. There wasobtained 94 gm. of a white solid (yield 72% with regard to theory)melting at 91 C.

The chemical analysis has given the following results:

Found (percent): N, 10.54; C, 46.28; H, 3.96; Cl, 27.05. Calculated(percent): N, 10.83; C, 46.0; H, 3.87; CI, 27.1.

Mass spectrometry and nuclear magnetic resonance indicate that thestructure of the obtained white solid corresponded to 2-methyl4-(3,4-di-chlorophenyl)-perhydro- 1,2,4-oxadiazine 3-one (product No.1).

In operating in the same conditions as hereinabove, from convenient rawmaterials there was prepared series of perhydro-1,2,4-oxadiazine 3-onesof Formula I the substituents R and R and the physical characteristicsof which are given in the Table 1 hereinafter (for those compounds,X=Y=CH TABLE 1 Product Meltin number R; R, point C.

3 CHP- Q 011 5 CHr- (ill 116 6 CzHr- 84 9 N-CKHP (II-@- on EXAMPLE 2 Ina flask provided with a central stirring, there was introduced 236 gm.(1 mole) of N-3,4-dichloro phenyl N'-methyl-N'-hydroxy urea and gm. (1.1mole) of monochloroacetyl chloride in solution in 2500 ml. of anhydrousacetone; then there was added slowly at a temperature not exceeding 10C., 101 gr. (1 mole) of triethyl-amine. After half an hour, the aminehydrochloride formed was removed by filtration. Then, at the temperatureof 20 C., an aqueous solution containing 40 gr. (1 mole) of sodiumhydroxide was poured slowly into the filtrate, the reaction mixturewhich first was neutral, suddenly became basified. At this time, icewater was added to the mixture, the formed precipitate recovered byfiltration and recrystallized from toluene. 205 g. of a white solidmelting at 122 C. was obtained. Mass spectrometery has shown that thisproduct structure corresponded to 2-methy1 4-(3,4-dichloro-phenyl)perhydro- 1,2,4-oxadiazine 3,6-dione (product No. 10).

Operating in the same conditions as above, starting from otherhydroxy-ureas, there were obtained other 1,2,4-oxadiazine-3,6-diones ofFormula 'I with Y=CO,

the structure and melting point of which are given in the followingTable 2.

In a flash provided with a central stirring there was introduced 236 g.(1 mole) of N-3,4-dichlorophenyl N-methy1-N'-hydroxy urea and 140 gr.(1.1 mole) of oxalyl chloride in solution in 2500 ml. of anhydrousacetone, then, at a temperature not exceeding 10 C., 202 gm. (2 moles)of triethyl amine was slowly added and after 11 hour the formed aminehydrochloride was removed by filtration. Ice water was added to thefiltrate, the formed precipitate was separated and recrystallized out ofa mixture of acetone/ water. There was obtained 172 gm. of a white solidmelting at 142 C., which, by analysis has shown itself to be 2-methyl4-(3,4-dichlorophenyl) 1,2,4-oxadiazine-3,5,6-trione (product No. 16).

EXAMPLE 4 Solutions of various heterocycles of the previous exampleswere prepared, by first dissolving the heterocycles in a polyalcoholether known under the name of Polygl'ycol 400 (that is the condensationproduct of ethylene oxide on one mole water, having a mean molecularweight of 400), then by diluting the solution in water in order toobtain concentrations of active ingredient varying between 1 and 50p.p.m. Then those solutions were sown with suspensions of a mixture ofunicellular green algae in which there was above all the speciesScenedesm us crassus; then nutritive extracts were added to the obtainedcompositions and every sample was placed in artificial light for 12 or24 hours at 25 C., during 8 days.

Thereafter either algae development or the absence of development orstill a partial development (i) were evaluated. The obtained results aregiven in the Table 3 hereinafter.

6 EXAMPLE 5 Product 10 of Example 2 was introduced, in various amounts,into a nitritive mixture which was sown with bacterium Staphylococcusaureus. The mixture was incubated at optimal conditions during a timenormally sufficient for bacteria development. This test provideddetermination of the minimal amount at which this product could beconsidered as being bacteriostatic. In order to know if it was also abactericide, an aliquot part from the previous test was then introducedinto a new nutritive mixture. Then, an absence of development of theactive product for a determined amount corresponded to the death of allthe present bacteria. The results of those bactericidal andbacteriostatic tests are given in Table 4, hereinafter, in which isindicated either bacterium development or the absence of development ora partial development (i).

TABLE 4 Efiicieney Bacteri- Bacteriostatie cidal Amount (p.p.m.)

IIIIII++ EXAMPLE 6 TABLE 5 Efiicieneywith regard to the amounts activeingredient (kg/1.) Product Stocks 5.10 1.10- 5.10 1.10

Polystictus uersicolor- Coniophora puteana.-.

IIIIIII- IlIlII Gyropham lacrymans- +H-lH-H-+ ++H-+++ +++l 1H- H-llllH-II-II-lIi-H-I-I- H'H-H-III IllIlI lllIll Chaetomium globasum-.

Steriamatocystis mgra- We claim: 1. An oxadiazine-trione of the formulao=o N--R1 in which R is alkyl of 1 to 5 carbon atoms or phenyl;References Cited and R is alkyl of 1 to 5 carbon atoms, phenyl, phenylmono-, di-, or tri-substituted with halogen, nitro, alkyl of UNITEDSTATES PATENTS 1 to 3 carbon atoms, or alkoxy of 1 to 3 carbon atoms or3,394,138 7/1968 Meen et 26O-244 phenyl mono-substituted withtrifluoromethyl.

2. An oxadiazine-trione according to claim 1 wherein 5 HARRY MOATZPnmary Exammer R is methyl.

3. An oxadiazine-trione according to claim 1 wherein R is3,4-dichlorophenyl.

4. An oxadiazine-trione according to claim 2 wherein 10 R is3,4-dichlorophenyl.

